Hyphenation of capillary electrophoresis (CE) with electrospray ionization mass spectrometry (MS) was developed in the late 1980s and has steadily developed since. Capillary electrophoresis-electrospray ionization interfaces generally fall into three categories: sheathless, co-axial sheath low, and liquid junction interfaces.
Sheath flow interfaces use a coaxial sheath liquid that mixes with analytes as they migrate from the separation capillary. The purpose of the sheath liquid is to provide electrical contact between the electrophoretic separation and the electrospray ionization source. Sheath liquid can also modify separation buffer to make it more compatible with MS detection. The sheath-flow interface originally developed is now commercially available. In that design, the distal end of the separation capillary is inserted inside a concentric tube, with the capillary's end extending beyond the tube. Electrical contact is made by a sheath liquid flowing over the capillary protruding from the tube, and a nebulizer gas is supplied to assist the spray formation. The sheath liquid needs to be pumped to maintain a stable spray and the interface operates at relatively high sheath flow rates, typically in the range of several microliters per minute, which can result in significant sample dilution.
In a liquid junction interface, the separation capillary and electrospray emitter are separated by a small gap. Electrical contact is made with this gap to drive the electrospray. Unfortunately, the gap can contribute to a loss of separation efficiency.
Sheathless interface designs eliminate sample dilution associated with the sheath liquid, which tends to result in higher sensitivity. In sheathless interfaces, the separation capillary often serves as the electrospray emitter. Ongoing research in the design of a sheathless interface mainly focuses on establishing electrical contact at the distal end of the separation capillary. Variations include coating the outer tip of the capillary with metal, inserting an electrode inside the capillary outlet, use of porous etched capillary walls, and the use of a microdialysis junction. The major drawbacks of sheathless interfaces are spray instability due to the very low flow rates produced in some separation conditions, and the limited choices of separation buffers due to lack of post column chemistry.
To overcome some of the problems associated with both the original sheath flow and sheathless interface designs, a low flow version of a sheath flow interface was introduced. In this design, the separation capillary was inserted inside a tapered glass emitter. A second capillary was inserted inside the emitter, supplying sheath liquid, pumped at the rate of 1 μL/min. Electrospray voltage was supplied by a stainless steel wire inserted into the emitter.
Sheath flow interfaces with tapered emitters can operate in the nanospray regime, which is associated not only with supporting lower flow rates but also with better desolvation, enhanced sensitivity, and increased salt tolerance. However, attempting to produce a nanospray from CE effluent presents many technical issues that must be overcome in order to advance the field of CE-MS